Abstract
By 1980, it was thought that we already knew most of the major mechanisms regulating vascular tone. However, after the somewhat serendipity discovery that endothelium is involved in mediation of relaxation to acetylcholine, a whole new world opened up and we had to rewrite our concept regarding vascular function and its regulation (not to mention many other fields). The new player was an endothelium derived relaxing factor, which molecular constitution has been identified to be nitric oxide (NO). This review summarizes the major molecular steps concerning how NO is synthetized from L-arginine. Also, the fate of L-arginine is described via the arginase and methylation pathways; both of them are affecting substantially the level and efficacy of NO. In vitro and in vivo effects of L-arginine are summarized and controversial clinical findings are discussed. On the basis of the use of methylated L-arginines, the vasomotor effects of endothelial NO released to agonists and increases in flow/wall shear stress (a major biological stimulus) is summarized. In this review the role of NO in the regulation of coronary vascular resistance, hence blood flow, is delineated and the somewhat questionable clinical use of NO donors is discussed. We made an attempt to summarize the biosynthesis, role, and molecular mechanisms of endogenously produced methylated L-arginine, asymmetric dimethylarginine (ADMA) in modulating vascular resistance, affecting the function of the heart. Additionally, the relationship between ADMA level and various cardiovascular diseases is described, such as atherosclerosis, coronary artery disease (CAD), ischemia/reperfusion injuries, and different types of coronary revascularization. A novel aspect of coronary vasomotor regulation is identified in which the pericardial fluid ADMA and endothelin play putative roles. Finally, some of the open possibilities for future research on L-arginine-NO-ADMA signaling are highlighted.
Highlights
After the original observation by Furchgott and Zawadzki (Furchgott and Zawadzki, 1980) it took more than a decade to identify the chemical nature and biochemical pathway of endothelium-derived relaxing factor (RF: “Robert Furchgott”) as it was called in the original paper
Since the discovery of the endothelium-derived relaxing factor by Furchgott and Zawadzki (1980) many investigations have been conducted both in basic science laboratories and clinical settings regarding the interaction between nitric oxide and coronary arteries or blood flow in healthy people and in patients with coronary artery disease
The present review covers recent developments in these investigations, including those reported over decades, on the roles of L-arginine and asymmetric dimethylarginine and endothelial and neural nitric oxide synthases (NOS) in the control of coronary circulation in healthy humans and those with coronary artery disease or cardiac ischemia and reperfusion injuries
Summary
After the original observation by Furchgott and Zawadzki (Furchgott and Zawadzki, 1980) it took more than a decade to identify the chemical nature and biochemical pathway of endothelium-derived relaxing factor (RF: “Robert Furchgott”) as it was called in the original paper. Based on the beneficial results of L-Arg supplementation observed in hypercholesterolemic rabbits, Clarkson et al confirmed the favorable effect of 3x7 g daily intake of this amino acid for 4 weeks on the endothelium-dependent vasodilatation in young patients with hypercholesterolemia (Clarkson et al, 1996) They measured the diameter of the brachial artery at rest, in response to reactive hyperemia, at rest afterwards and after the administration of sublingual nitroglycerin. SMTC had no effect on substance P- and pacing-induced increases in CBF, these responses were significantly attenuated by the nonselective NOS inhibitor LNMMA, suggesting the involvement of eNOS but not nNOS (Seddon et al, 2009; Shabeeh et al, 2013) These data show that eNOS and nNOS play different local roles in the control of human coronary circulation in vivo. ADMA is mainly metabolized in the kidney and the liver (Nijveldt et al, 2003a; Nijveldt et al, 2003b)
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